PROJECT SUMMARY Antimicrobial resistance is one of the greatest threats to human health worldwide. Just one organism, methicillin-resistant Staphylococcus aureus (MRSA), kills more U.S. citizens than HIV/AIDS, emphysema, Parkinson?s disease, and homicide combined. While new strategies to treat or prevent antibiotic-resistant infections are at the healthcare forefront, treatment for recalcitrant or recurring wound infections and neglected tropical diseases, such as Buruli ulcer, are also greatly needed. As many as 100,000 deaths and costs of $3.5B annually are associated with wound infections. With a lack of new drug candidates in the pipeline and the ability of bacteria to rapidly develop resistance to narrow and broad-spectrum antibiotics, we are exploring complementary and integrative strategies to combat cutaneous bacterial infections. We have previously demonstrated that iron and copper metal ions mediate in vitro antibacterial activity associated with natural clays. However, due to vast antibacterial and chemical variability of natural clays, control of chemical, structural, and surface properties of aluminosilicates is necessary for biomedical applications. The current proposal specifically aims to develop hierarchical, nanosized, and nanostructured zeolites impregnated with Ag+, Cu2+, or Fe2+ metal ions to mediate localized delivery of antibacterial ions. These ion-exchanged nanozeolites will be synthesized and examined for bactericidal potential against MRSA and Mycobacterium ulcerans, the causative agent of Buruli ulcer, for the ability to disrupt MRSA biofilms, and for cytotoxicity against macrophages, fibroblasts, and epithelial cells. In addition to nanozeolite-mediated localized release of active bactericidal ions, we will develop porous geopolymers modified to exhibit variations in surface hydrophobicity, hydrophilicity, and charge. These surface-modified geopolymers will be investigated for the ability to adsorb bacteria (MRSA and M. ulcerans), bacterial proteins, and specific toxins secreted by these bacteria. We hypothesize that the surface-modified geopolymers will adsorb bacteria, toxins, and exudate within infected wounds and mediate physical removal via dressing changes and non-surgical adsorptive debridement. These studies will provide important preclinical results designed to optimize materials for in vivo efficacy and beneficial effects on wound closure and healing. The proposed research is relevant to the NIH mission designed to improve human health by fostering fundamental discoveries related to the cause, prevention, and cure of human diseases and to national efforts ensuring a steady pipeline of new and effective therapeutic strategies to combat infectious agents.